CardioRenal Syndrome

Dr Hussein Bagha FRCP(Edin)

Consultant Physician and Nephrologist
Case 1
• 64 yr old female known to have CAD, DM, HTN, CKD &
hypothyroidism
• PCI in 2011
• CABG in June 2016
• Atorvastatin/ezetemibe, ASA, clopidogrel, telmisartan, amlodipine,
bisoprolol, torsemide and insulin glargine
• Serum creatinine post CABG – 131 micromoles/l
• Presented with a one day history of DOE and orthopnea
• In RD with coarse creps bilaterally
• BP 211/93, HR 101/min SPO2 98%
• ECG – Old LBBB
• UECs – 136/5.5/101/12.8/194
• eGFR – 23 mls/min (CKD EPI)
• CBC – 9/11/235
• Pro BNP - 19,000
• Troponin - 40
• 2D echo - LVEF 40%, apical, septal & posterior wall hypokinesia,
severe MR, moderate TR with PASP of 40 mmHg
• Urinalysis - protein +, no cells, no glucose (no change from previous
urinalysis in 2016)
• Admitted to the ICU
Treatment:
•IV furosemide 40 mg twice daily
•Insulin dextrose
•IV GTN infusion
•Telmisartan was held
•Urine output was 200 mls in 12 hours
•Serum creatinine 274 micromol/l
• Does this patient have
Cardiorenal syndrome type 1
Cardiorenal syndrome type 2
Cardiorenal syndrome type 3
Cardiorenal syndrome type 4
Cardiorenal syndrome type 5
Definition
• Difficult to define as it encompasses complex multifactorial facets including
physiological, biochemical and hormonal

• Following a consensus conference in 2008, the report defines CRS as

‘disorders of the heart & kidneys whereby acute or chronic dysfunction in
one organ may induce acute or chronic dysfunction of the other’

• It is not static

Ronco et al 2008
Cardiorenal Syndrome (CRS) General Definition:
A pathophysiologic disorder of the heart and kidneys whereby acute or chronic
dysfunction in one organ may induce acute or chronic dysfunction in the other
organ

CRS Type I (Acute Cardiorenal Syndrome)

Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or
decompensated congestive heart failure) leading to acute kidney injury
CRS Type II (Chronic Cardiorenal Syndrome)
Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure)
causing progressive and permanent chronic kidney disease
CRS Type III (Acute Renocardiac Syndrome)
Abrupt worsening of renal function (e.g. acute kidney ischaemia or
glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia,
ischemia)

CRS Type IV (Chronic Renocardiac Syndrome)

Chronic kidney disease (e.g. chronic glomerular disease) contributing to
decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse
cardiovascular events

CRS Type V (Secondary Cardiorenal Syndrome)

Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and
renal dysfunction

Ronco C et al. J Am Coll Cardiol 2008; 52: 1527-39

Clinical Importance
• Mortality is increased in pts with heart failure who
have a reduced glomerular filtration rate
• Pts with CKD have an increased risk of both ASCVD
and heart failure, and cardiovascular disease is
responsible for up to 50% of deaths in pts with renal
failure
• Acute or chronic systemic disorders can cause both
cardiac and renal dysfn

Coresh J et al. prevalence of chronic kidney disease and decreased kidney function in the adult US population:
Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003; 41:1.
Baseline Kidney Function as Predictor of CV Mortality/HF
Hospitalization
Creatinine BUN

2nd vs 1st 3rd vs 1st 4th vs 1st 2nd vs 1st 3rd vs 1st 4th vs 1st
quartile quartile quartile quartile quartile quartile

1.32 1.55 1.68 1.15 1.25 1.50

3-months 3 months
(1.05-1.65) (1.21-1.98) (1.32-2.13) (0.90-1.46) (0.99-1.57) (1.19-1.88)

1.10 1.37 1.50 1.08 1.20 1.60

Overall Overall
(0.95-1.28) (1.16-1.61) (1.28-1.76) (0.91-1.27) (1.02-1.41) (1.36-1.87)

Adjusted for: Age, Race, Region, HF hospitalization, Previous MI, Diabetes, Dyspnea, NYHA Class,
ACE/ARB, Beta Blockers, Systolic BP, EF, Serum Sodium, BNP, Pro-BNP, QRS Duration, and Atrial 13
Fibrillation on admission

Gheorghiade M, et al: ESC, 2008

Association Between eGFR (CKD-EPI) and All-Cause Mortality in Patients with HF, Grouped by LVEF

McAlister F A et al. Circ Heart Fail 2012;5:309-314

Association of Chronic Kidney Disease with Clinical Outcomes in Patients with
HFpEF

Unger ED, et al. European Journal of Heart Failure. (2016) 18, 103–112
Next step?
•Increase furosemide to 80 mg BD
•Add tolvaptan
•Stop GTN and change to nesiritide
•Dialysis & ultrafiltration
•Low dose dopamine
• Furosemide was increased to 80 mg twice daily
• Continued with GTN infusion
• Serum potassium reduced to 4.8 mmol/L
• Urine output increased to 1.2 L/24 hrs
• Pts symptoms improved
• Serum creatinine progressively increased – peaked on 5th day of
admission to 417 micromoles/L
• Serum creatinine decreased to 270 micromoles/L on 10th day post
admission
• Serum K was normal
• eGFR 16mls/min
• Symptoms improved
• Ambulating
• BPs persistently high
Next Step?
• Re-start telmisartan
• Change to enalapril
• Start sacubitril/valsartan
• Opt not to start ACEI or ARB/ARNi as the eGFR is 16 mls/min
Sacubitril/valsartan led to a modest increase
in UACR compared with enalapril
• Increase in UACR from screening to randomization remained elevated in the
sacubitril/valsartan group, but returned to the screening level in enalapril group

1.50
P <0.001* P <0.001*

1.25

UACR (mg/mmol) 1.00

0.75

0.50
Enalapril
0.25 Sacubitril/valsartan

0.00
Screening Randomization 1 Month 8 Months

*P-value between treatment groups

Damman et al., JACC Heart Fail. 2018 DOI:

UACR, urine albumin-to-creatinine ratio; vs, versus 10.1016/j.jchf.2018.02.004
Business Use Only 26
Sacubitril/valsartan-associated modest increase in UACR is
likely to be mediated by NPs

• It is likely that the rapid onset and modest increase in UACR, which stabilized
after a few weeks of treatment with sacubitril/valsartan, reflects a distinct,
and probably acute intra-renal hemodynamic effect 1
̶ This effect is probably due to actions of natriuretic peptides (and possibly
other vasoactive substrates of neprilysin)1-6

Increase in glomerular Alterations in renal

endothelial permeability Possibilities
arteriolar tone
and hydraulic conductivity include one or
more of these
three
mechanisms1-6
Direct effect on
mesangial cells
1. Damman et al., JACC Heart Fail. 2018 DOI: 10.1016/j.jchf.2018.02.004; 2. McMurray et al. J
Hypertens. (1988); 6:783−6; 3. Axelsson et al. Am J Physiol Renal Physiol. (2011); 300:F24-30;
NP, natriuretic peptides; UACR, urinary 4.Vervoort et al., Am J Kidney Dis. (2002) 40:9−15; 5. Prasad et al., Diabet Med. (1998;)15:678-82 ; 6.
albumin to creatinine ratio
Business Use Only
Lofton et al. Biochem Biophys Res Commun. (1990);172:793-9
27
Circulation. 2018 Oct 9;138(15):1505-1514.
UK HARP III Trial
• Randomized double blind trial
• 414 participants with CKD stage 3 and 4
• Irbesartan versus sacubitril/valsartan
• 1o outcome – eGFR at 12 months
• Over 12 months sacubitril/valsartan had similar effects on kidney fn &
albuminuria to irbesartan but it has the additional effects of lowering
BP and cardiac biomarkers in CKD

Circulation. 2018 Oct 9;138(15):1505-1514.

Circulation. 2018 Oct 9;138(15):1505-1514.
Case 2
• 64 year old male
• Re-admission – progressive DOE NYHA class III
• Admitted one month before due to a cardiac arrest 2o to anterolateral
STEMI
• PCI done
• Was on aspirin, ticagrelor, atorvastatin, carvedilol and ivabradine
• Developed a complete heart block
• Temporary pacemaker inserted
• Beta blocker and ivabradine was stopped
• Heart block resolved
• On discharge, EF 30%
• Current admission – BP 110/80, HR 88/min, SPO2 96%
• Had bibasal crackles with an elevated JVP
• Pro BNP 12,000
• UECs normal
• Started on IV furosemide 40 mg twice daily
• Fluid restriction
• Noted to have worsening renal fn – Cr 160 micromoles/L
• 2D echo – EF 20%, same pattern of RWMA as previous echo
• Had symptomatic improvement after two days of IV furosemide
• Hemodynamically stable
• Started on sacubitril/valsartan (24/26)
• Pts BP dropped – 80/50 mm/Hg
• The sacubitril/valsartan was stopped
• Patient’s BPs stabilised at 90/60 mmHg
• Was discharged on furosemide, atorvastatin, aspirin and ticagrelor
• Was seen as an outpatient and BPs were stable
• He was started on sacubitril/valsartan 50 mg OD
• Tolerated it well
• Increased to twice daily
• BPs are stable
• Pts symptoms have improved - NYHA II
• 2D echo – LVEF 30%
• Can’t tolerate a higher dose than 50 mg twice daily
• How common is hospital admission for worsening renal function in
pts with heart failure & what are the challenges faced in
individualization of their Rx
• More common to get kidney complications requiring intervention in
pts admitted with heart failure
• Not common cause of admission
• Hyperkalemia most common complication
• Challenges:
1.Optimal dose of diuretic therapy vs worsening renal fn
2.ACEi/ARBs and rise in Cr
3.BP control
4.Worsening heart failure
Case 3
• 51 yr old female with no known comorbids
• H/o left orbital meningioma excised in 2017
• C/o cough for one month, associated with DOE NYHA
II-III
• Intermittent lower limb edema with orthopnea for
one month
• Being treated for asthma (family h/o asthma)
• Not a known diabetic or hypertensive
• No h/o smoking/drinking alcohol
Examination
• Sick looking
• BP 119/87, HR 105/min, SPO2 90%, RR 26/min
• Pedal edema to the shin
• RS Crackles mid and lower lung zones bilaterally
• CVS JVP high, diffuse apex, loud S2, PSM in the apical and LLSB areas
• PA Hepatomegally 4 cm BCM
Ix
• CBC 9.73/14.3/369
• CRP 4.35
• UECs 143/4.08/105/4.12/96
• LFTs normal
• ProBNP 4278
• Troponins 37
• HbA1c 5.8%
Ix
• Lipid profile normal
• 12 lead ECG – sinus rhythm, rate 106/min. Q waves V2, V3, V4
• 2D echo – LV global wall hypokinesia with severely impaired LVEF
30%, diastolic type II dysfunction, dilated LA, severe MR/TR, normal
valve morphology, severe PAH – RVSP 60 mmHg
• HRCT – cardiogenic pulmonary edema
• Coronary angiogram – left main – patent with good flow, LAD –
patent with slow flows, D1 100% stenosis mid segment, left
circumflex – patent, RCA – non-dominant, patent with good flow
Treatment
• Aspirin 300 mg stat then 75 mg OD
• Clopidogrel 300 mg stat then 75 mg OD
• IV furosemide 20 mg BD
• Atorvastatin 80 mg OD
• Ramipril 2.5 mg BD
• Enoxaparin 80 mg SC BD
• Symptoms improved
• Off oxygen
• Started on carvedilol 3.125 mg BD
• Stopped ramipril
• Started on sacubitril/valsartan 50 mg BD
• Discharged on: furosemide 40 mg BD, sacubitril/valsartan 50 mg BD,
Asa 75 mg OD, clopidogrel 75 mg OD, atorvastatin 80 mg nocte,
carvedilol 3.15 mg BD
Follow up
• Review in 2 weeks: UECs normal, reporting improvement in
symptoms, sacubitril/valsartan increased to 100 BD
• Review after one month: UECs normal, symptoms significantly
improved– DOE NYHA II, sacubitril/valsartan increased to 200 BD
• Review after 2 month – 2D echo: EF 35% (30%)
• ProBNP 800 (4278)
• Review after six month:
• Reports significant improvement of her symptoms
• Orthopnea has resolved
• NYHA class II
• Serum potassium and creatinine remain stable
• Repeat 2D echo – LVEF – 40%, PASP 40 mmHg, mild TR, moderate MR
PROVE HF
PIONEER HF Trial
• Multicenter, randomized, double blind, active-controlled
trial
• 129 sites in the US
• Pts with ADHF and HFrEF were randomized to
sacubitril/valsartan or enalapril after hemodynamic
stabilization
• 440 pts randomized to receive sacubitril/valsartan and
441 received enalapril
• Io efficacy outcome was the time-averaged proportional
change in the NT ProBNP
• Key safety outcomes were rates of worsening renal fn,
hyperkalemia, symptomatic hypotension & angioedema
Changes in NT ProBNP Concentration
Secondary and Safety Outcomes
Pioneer HF Trial
• In an analysis of exploratory clinical outcomes, the in-hospital
initiation of sacubitril–valsartan therapy was associated with a lower
rate of re-hospitalization for heart failure at 8 weeks than enalapril
therapy
 Cardio-Renal Mechanisms in Acute Heart Failure
Ventricular
Vasodilation and Natriureisis
Right Heart Shift Left Heart LVEDP
+ Down Regulation
Dysfunction Pericardial Dysfunction NP Receptors
Constraint

SV Prostacyc
CVP Kinnin NP NO
lin
CO

Vasopres RAAS and SNS response

RAAS SNS ET-1
sin overwhelms NP and NO
response
Vasoconstriction & Sodium + Water
Retention Adenosine
Renal Vein
Pressure
Inflamma
tion

Interstial Decreased Renal

Edema Perfusion / Ischemia

Acute Kidney Intrinsic Renal

Injury Disease

ACE-I
NSAIDs RAS Contrast
ARB

Kiernan MS, Udelson JE, Sarnak M, Konstam MA: Cardiorenal syndrome UpToDate
 Conclusions
• The cardio-renal syndrome is complex, related to both diminished
renal perfusion and increased venous pressure.
• Therapies should target neuro-humoral modulation
• ARNIs have been shown to reduce mortality when added to the usual
therapies in HFrEF
• Can be started in pts with heart failure before discharge
• ARNIs help to stabilize and improve renal function in patients with
cardiorenal syndrome